Targeting Serotonin Transporters in the Treatment of Juvenile and Adolescent Depression

Depression is a serious public health concern. Many patients are not effectively treated, but in children and adolescents this problem is compounded by limited pharmaceutical options. Currently, the Food and Drug Administration approves only two antidepressants for use in these young populations. Both are selective serotonin reuptake inhibitors (SSRIs). Compounding matters further, they are therapeutically less efficacious in children and adolescents than in adults. Here, we review clinical and preclinical literature describing the antidepressant efficacy of SSRIs in juveniles and adolescents. Since the high-affinity serotonin transporter (SERT) is the primary target of SSRIs, we then synthesize these reports with studies of SERT expression/function during juvenile and adolescent periods. Preclinical literature reveals some striking parallels with clinical studies, primary among them is that, like humans, juvenile and adolescent rodents show reduced antidepressant-like responses to SSRIs. These findings underscore the utility of preclinical assays designed to screen drugs for antidepressant efficacy across ages. There is general agreement that SERT expression/function is lower in juveniles and adolescents than in adults. It is well established that chronic SSRI treatment decreases SERT expression/function in adults, but strikingly, SERT expression/function in adolescents is increased following chronic treatment with SSRIs. Finally, we discuss a putative role for organic cation transporters and/or plasma membrane monoamine transporter in serotonergic homeostasis in juveniles and adolescents. Taken together, fundamental differences in SERT, and putatively in other transporters capable of serotonin clearance, may provide a mechanistic basis for the relative inefficiency of SSRIs to treat pediatric depression, relative to adults

Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice

Abstract word count: 250 Introduction word count: 74

Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways

Early exposure to ketamine does not affect nicotine reward during adolescence in male and female rats

Children are commonly prescribed fluoxetine to manage their depressive symptoms, although evidence suggests many fail to respond to this treatment. Recently, low doses of ketamine were shown to work as a fast-acting and long-lasting antidepressant, however, it is unclear what the long-term effects are of using ketamine in pediatric populations. Thus, this thesis examined whether early-life exposure to ketamine influences the rewarding effects of nicotine in male and female adolescent Sprague-Dawley rats using conditioned place preference. Rats were pretreated with ketamine (0.0 or 20.0 mg/kg) from postnatal day (PD) 21-30 and then assessed for nicotine (0.0, 0.03, 0.1, 0.3, or 0.6 mg/kg) preference during adolescence (PD 32-42). Results indicate that female adolescent rats find nicotine to be more rewarding than male rats, however ketamine pretreatment did not affect nicotine’s effects. These findings suggest that ketamine as an antidepressant in children and adolescents may not produce adverse increases in nicotine reward